The present invention provides oxazinocarbazole derivatives having a ring connecting position 8 (C-8) and position 9 (N-9), and more specifically, provides compounds of formula (I) described herein below. These compounds are 5-HT ligands, and are useful for treating diseases wherein modulation of 5-HT activity is desired.
Many diseases of the central nervous system are influenced by the adrenergic, the dopaminergic, and the serotonergic neurotransmitter systems. For example, serotonin has been implicated in a number of diseases and conditions which originate in the central nervous system. These include diseases and conditions related to sleeping, eating, perceiving pain, controlling body temperature, controlling blood pressure, depression, anxiety, schizophrenia, and other bodily states. R. W. Fuller, Biology of Serotonergic Transmission, 221 (1982); D. J. Boullin, Serotonin in Mental Abnormalities 1:316 (1978); J. Barchas, et al., Serotonin and Behavior, (1973). Serotonin also plays an important role in peripheral systems, such as the gastrointestinal system, where it has been found to mediate a variety of contractile, secretory, and electrophysiologic effects.
As a result of the broad distribution of serotonin within the body, there is a tremendous interest in drugs that affect serotonergic systems. In particular, receptor-specific agonists and antagonists are of interest for the treatment of a wide range of disorders, including anxiety, depression, hypertension, migraine, obesity, compulsive disorders, schizophrenia, autism, neurodegenerative disorders (e.g. Alzheimer""s disease, Parkinsonism, and Huntington""s chorea), and chemotherapy-induced vomiting. M. D. Gershon, et al., The Peripheral Actions of 5-Hydroxytryptamine, 246 (1989); P. R. Saxena, et al., Journal of Cardiovascular Pharmacology, 15: Supplement 7 (1990).
The major classes of serotonin receptors (5-HT1-7) contain fourteen to eighteen separate receptors that have been formally classified. See Glennon, et al., Neuroscience and Behavioral Reviews, 1990, 14, 35; and D. Hoyer, et al. Pharmacol. Rev. 1994, 46, 157-203. Recently discovered information regarding subtype identity, distribution, structure, and function suggests that it is possible to identify novel, subtype specific agents, having improved therapeutic profiles (e.g. fewer side effects).
For example, The 5-HT6 receptor was identified in 1993 (Monsma et al. Mol. Pharmacol. 1993, 43, 320-327 and Ruat, M. et al. Biochem. Biophys. Res. Com. 1993, 193, 269-276). Several antidepressants and atypical antipsychotics bind to the 5-HT6 receptor. with high affinity and this binding may be a factor in their profile of activities (Roth et al. J. Pharm. Exp. Therapeut. 1994, 268, 1403-1410; Sleight et al. Exp. Opin. Ther. Patents 1998, 8, 1217-1224; Bourson et al. Brit. J. Pharm. 1998, 125, 1562-1566; Boess et al. Mol. Pharmacol. 1998, 54, 577-583; Sleight et al. Brit. J. Pharmacol. 1998, 124, 556-562). In addition, the 5-HT6 receptor has been linked to generalized stress and anxiety states (Yoshioka et al. Life Sciences 1998, 17/18, 1473-1477). Together these studies and observations suggest that compounds that antagonize the 5-HT6 receptor will be useful in treating disorders of the central nervous system.
Compounds of the present invention are 5-HT ligands (e.g. receptor-spedific agonists or antagonists). Thus they are useful for treating diseases wherein modulation of 5-HT activity is desired. Specifically, the compounds of this invention are useful in the treatment of psychosis, paraphrenia, psychotic depression, mania, schizophrenia, schizophreniform disorders, anxiety, migraine headache, drug addiction, convulsive disorders, personality disorders, post-traumatic stress syndrome, alcoholism, panic attacks, obsessive-compulsive disorders, and sleep disorders. The compounds of this invention are also useful to treat psychotic, affective, vegetative, and psychomotor symptoms of schizophrenia and the extrapyramidal motor side effects of other antipsychotic drugs. This last action will allow higher doses of antipsychotics to be used and thus greater antipsychotic efficacy to be obtained as a result of a reduction in side effects. The compounds of this invention are also useful in the modulation of eating behavior and thus are useful in treating excess weight and associated morbidity and mortality.
International Publication No. WO97/45427 discloses pyridocarbazole derivatives having a highly selective cyclic GMP-phosphodiesterease inhibitory effect.
International Publication No. WO95/11245 discloses tetracyclic indole derivatives which have a selective antagonism against intestinal 5-HT3 receptors and are useful for preventing or treating digestive tract disorders such as irritable bowel syndrome and diarrhea.
Abstracts of SU-256776-S, SU-252342-S and SU-255278-S disclose 1,2-dihydropyrazino carbazoles useful as intermediates in the synthesis of biologically active compounds.
European Patent Application EP 377238 discloses annelated indolo [3,2-c] lactam derivatives having an antagonistic activity on 5-HT receptors. The compounds can be used for the treatment gastrointestinal system disorders, central nervous system disorders, cardiovascular disorders, respiratory system disorders, and for alleviating or preventing withdrawal symptoms which are induced by abuse of drugs.
European Patent Application EP 344015 discloses tetracyclic ketones useful in the treatment of psychotic disorders, anxiety, nausea, and vomiting in which a cyclohexanone ring system is fused to an indole system.
European Patent Application EP 297651 discloses tetracyclic ketones useful as antagonists of serotonin receptors in which a cyclohexanone ring system is attached to an indole system.
The present invention provides a compound of formula I 
or a pharmaceutically acceptable salt thereof wherein
R1 is
(a) H,
(b) halo, or
(c) C1-6 alkyl;
R2 is
(a) H,
(b) halo,
(c) xe2x80x94OH,
(d) xe2x80x94CN,
(e) xe2x80x94CF3,
(f) xe2x80x94O(C1-6)alkyl,
(g) C1-6 alkyl,
(h) C3-6 cycloalkyl,
(i) xe2x80x94NR5R6,
(j) xe2x80x94CONR5R6,
(k) xe2x80x94SO2NR5R6,
(l) xe2x80x94COOR7, or
(m) phenyl, optionally substituted with halo, OH, O(C1-4) alkyl, or C1-6 alkyl;
R3 is
(a) xe2x80x94(CH2)mxe2x80x94NR8R9 wherein the xe2x80x94(CH2)mxe2x80x94 chain may be substituted with one or two C1-6 alkyl or C3-6 cycloalkyl;
R4 is
(a) aryl, or
(b) heteroaryl;
aryl is phenyl or naphthyl, optionally substituted with one or more R10;
hetetoaryl is a radical of a five- or six-membered monocyclic aromatic ring having one or two heteroatoms each selected from the group consisting of oxygen, sulfur, and N(X), or a radical of a nine- or ten-membered ortho-fused bicyclic aromatic ring having one, two or three heteroatoms each selected from the group consisting of oxygen, sulfur, and N(X);
wherein X is absent, H or C1-4 alkyl; wherein carbon atoms of heteroaryl may be substituted with one or more R10;
R5 and R6 is independently
(a) H,
(b) C1-6 alkyl, or
(c) C3-6 cycloalkyl;
R7is
(a) C1-6 alkyl, or
(b) (C1-3 alkyl)-phenyl wherein phenyl may be substituted with R10;
R8 and R9 is independently
(a) H,
(b) C1-6 alkyl,
(c) C3-6 cycloalkyl,
(a) C2-4 alkyl substituted with xe2x80x94OH, xe2x80x94O(C1-4 alkyl), xe2x80x94O(C1-4 alkyl)xe2x80x94NR11R12, or xe2x80x94CO2R5,
(e) xe2x80x94CHO, with the proviso that only one of the R8 and R9 is CHO, the other one is hydrogen,
(f) xe2x80x94(CH2)m-phenyl wherein the phenyl may be substituted with halo, or
(g) R8 and R9 taken together with the nitrogen to which they are attached form a five-, six-, or seven-membered heterocyclic ring wherein the heterocyclic ring optionally has one to two additional heteroatoms selected from the group consisting of oxygen, sulfur and N(Y) and wherein the carbon atoms of the heterocyclic ring is optionally substituted with one or two R13;
Y is absent or R14;
R10 is
(a) halo,
(b) xe2x80x94OH,
(c) xe2x80x94CN,
(d) xe2x80x94CF3,
(e) xe2x80x94O(C1-6)alkyl,
(f) C1-6 alkyl,
(g) C3-6 cycloalkyl,
(h) xe2x80x94NR5R6,
(i) xe2x80x94CONR5R6,
(j) xe2x80x94SO2NR5R6,
(k) xe2x80x94COOR7, or
(l) phenyl, optionally substituted with halo, OH, O(C1-4) alkyl, or C1-6 alkyl;
R11 and R12 is independently,
(a) H, or
(b) C1-4 alkyl;
R13 is
(a) C1-6 alkyl,
(b) C3-6 cycloalkyl,
(c) C2-4 alkyl substituted with xe2x80x94OH, xe2x80x94O(C1-4 alkyl), xe2x80x94O(C1-4 alkyl)xe2x80x94NR10R11, or xe2x80x94CO2R5,
(d) xe2x80x94OH, or
(e) oxo (xe2x95x90O);
R14 is
(a) H,
(b) C1-6alkyl,
(c) C3-6 cycloalkyl,
(d) C2-4 alkyl substituted with xe2x80x94OH, xe2x80x94O(C1-4 alkyl), xe2x80x94O(C1-4 alkyl)xe2x80x94NR10R11, or xe2x80x94CO2R5,
(e) xe2x80x94COOR7,
(f) xe2x80x94OH, or
(g) oxo (xe2x95x90O);
and m is 2, 3 or 4.
The present invention further provides a pharmaceutical composition comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In preferred embodiments, the composition preferably comprises a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.
The present invention further provides a method for treating a disease or condition in a mammal wherein a 5-HT receptor is implicated and modulation of a 5-HT function is desired comprising administering to the mammal a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof.
The present invention further provides a method for treating a disease or condition in a mammal wherein a 5-HT6 receptor is implicated and modulation of a 5-HT6 function is desired comprising administering to the mammal a therapeutically effective amount of a compound of formula III, or a pharmaceutically acceptable salt thereof;
The present invention further provides a method for treating or preventing diseases or disorders of the central nervous system comprising administering a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof to the mammal. Diseases or disorders for which a compound of formula I may have activity include, but are not limited to the following: obesity, depression, schizophrenia, schizophreniform disorder, schizoaffective disorder, delusional disorder, a stress related disease (e.g. general anxiety disorder), panic disorder, a phobia, obsessive compulsive disorder, post-traumatic-stress syndrome, immune system depression, a stress induced problem with the urinary, gastrointestinal or cardiovascular system (e.g., stress incontinence), neurodegenerative disorders, autism, chemotherapy-induced vomiting, hypertension, migraine headaches, cluster headaches, sexual dysfunction in a mammal (e.g. a human), addictive disorder and withdrawal syndrome, an adjustment disorder, an age-associated learning and mental disorder, anorexia nervosa, apathy, an attention-deficit disorder due to general medical conditions, attention-deficit hyperactivity disorder, behavioral disturbance (including agitation in conditions associated with diminished cognition (e.g., dementia, mental retardation or delirium)), bipolar disorder, bulimia nervosa, chronic fatigue syndrome, conduct disorder, cyclothymic disorder, dysthymic disorder, fibromyalgia and other somatoform disorders, generalized anxiety disorder, an inhalation disorder, an intoxication disorder, movement disorder (e.g., Huntington""s disease or Tardive Dyskinesia), oppositional defiant disorder, peripheral neuropathy, post-traumatic stress disorder, premenstrual dysphoric disorder, a psychotic disorder (brief and long duration disorders, psychotic disorder due to medical condition, psychotic disorder NOS), mood disorder (major depressive or bipolar disorder with psychotic features) seasonal affective disorder, a sleep disorder, a specific developmental disorder, agitation disorder, selective serotonin reuptake inhibition (SSRI) xe2x80x9cpoop outxe2x80x9d syndrome or a Tic disorder (e.g., Tourette""s syndrome).
The present invention further provides a method for treating anxiety, depression or stress related disorders ministering a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof to the mammal.
The present invention further provides the use of a compound of formula I or a pharmaceutically acceptable salt thereof to prepare a medicament for treating or preventing diseases or disorders of the central nervous system.
The present invention further provides a method for modulating 5-HT receptor function, comprising contacting (in vitro or in vivo) the receptor with an effective inhibitory amount of a compound of formula I or a pharmaceutically acceptable salt thereof.
The invention also provides novel intermediates and processes for preparing compounds of formula I.
The compounds of the present invention are generally named according to the IUPAC or CAS nomenclature system. Abbreviations which are well known to one of ordinary skill in the art may be used (e.g. xe2x80x9cPhxe2x80x9d for phenyl, xe2x80x9cMexe2x80x9d for methyl, xe2x80x9cEtxe2x80x9d for ethyl, xe2x80x9chxe2x80x9d for hour or hours and xe2x80x9crtxe2x80x9d for room temperature).
The carbon atom content of various hydrocarbon-containing moieties is indicated by a prefix designating the minimum and maximum number of carbon atoms in the moiety, i.e., the prefix Ci-j indicates a moiety of the integer xe2x80x9cixe2x80x9d to the integer xe2x80x9cjxe2x80x9d carbon atoms, inclusive. Thus, for example, C1-7alkyl refers to alkyl of one to seven carbon atoms, inclusive.
Specific and preferred values listed below for radicals, substituents, and ranges, are for illustration only; they do not exclude other defined values or other values within defined ranges for the radicals and substituents.
The following definitions are used, unless otherwise described.
Halo is fluoro, chloro, bromo, or iodo.
Alkyl denotes both straight and branched groups; but reference to an individual radical such as xe2x80x9cpropylxe2x80x9d embraces only the straight chain radical, a branched chain isomer such as xe2x80x9cisopropylxe2x80x9d being specifically referred to. Specifically, C1-7 alkyl can be methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, sec-butyl, pentyl, 3-pentyl, or hexyl.
C3-6 cycloalkyl denotes a cycloalkyl having three to six carbon atoms. Specifically, C3-6 cycloalkyl can be cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
Aryl denotes a phenyl or a naphthyl radical. Optionally, aryl is substituted with one or more halo, OH, CN, CF3, O(C1-6)alkyl, C1-6 alkyl, C3-6 cycloalkyl, NR5R6, CONR5R6, SO2NR5R6, COOR7, or phenyl which in turn may be substituted with halo, OH, O(C1-4) alkyl, or C1-6 alkyl.
Heteroaryl denotes a radical of a five- or six-membered monocyclic aromatic ring having one or two heteroatoms each selected from the group consisting of oxygen, sulfur, and N(X), or a radical of a nine- or ten-membered ortho-fused bicyclic aromatic ring having one, two or three heteroatoms each selected from the group consisting of oxygen, sulfur, and N(X); wherein X is absent, H or C1-4 alkyl; wherein carbon atoms of heteroaryl may be substituted with one or more halo, OH, CN, CF3, O(C1-6)alkyl, C1-6 alkyl, C3-6 cycloalkyl, NR5R6, CONR5R6, SO2NR5R6, COOR7, or phenyl which in turn may be substituted with halo, OH, O(C1-4) alkyl, or C1-6alkyl. Specifically, heteroaryl can be pyridyl, thiophene, benzothiophene, benzofuran, benzimidazole, imidazole or thiazole.
Pharmaceutically acceptable salts denotes acid addition salts useful for administering the compounds of this invention and include hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, acetate, propionate, lactate, mesylate, maleate, malate, succinate, tartrate, citric acid, 2-hydroxyethyl sulfonate, fumarate, methanesulfonic acid salt and etc. Specifically, pharmaceutically acceptable salts can be maleate, methanesulfonic acid salt and etc.
Mammal denotes human and animals.
A specific value for R1 includes H, halo, or C1-6 alkyl.
A specific value for R1 includes H or chloro.
A specific value for R2 includes H, halo, xe2x80x94OH, xe2x80x94CN, xe2x80x94CF3, xe2x80x94O(C1-6)alkyl, C1-6 alkyl, C3-6 cycloalkyl, xe2x80x94NR5R6, xe2x80x94CONR5R6, xe2x80x94SO2NR5R6, xe2x80x94COOR7, or phenyl which may be substituted with halo, xe2x80x94OH, xe2x80x94O(C1-4) alkyl, or C1-6 alkyl; wherein R5 and R6 is H, C1-6 alkyl, or C3-6 cycloalkyl; wherein R7 is C1-6 alkyl, or (C1-3 alkyl)-phenyl wherein phenyl may be substituted with R2.
A specific value for R2 includes H, halo, or C1-6 alkyl.
A specific value for R2 includes H, choro, fluoro, or methyl.
A specific value for R2 includes H, or methyl.
A specific value for R3 includes xe2x80x94(CH2)mxe2x80x94NR8R9, wherein the xe2x80x94(CH2)mxe2x80x94 chain may be substituted with one or more C1-6 alkyl or C3-6 cycloalkyl; wherein R8 and R9 is independently H, C1-6 alkyl, C3-6 cycloalkyl, C2-4 alkyl substituted with OH, xe2x80x94O(C1-4 alkyl), xe2x80x94O(C1-4 alkyl)xe2x80x94NR10R11 or xe2x80x94CO2R5, xe2x80x94CHO (with the proviso that only one of the R8 and R9 is xe2x80x94CHO, the other one is hydrogen), xe2x80x94(CH2)m-phenyl wherein the phenyl may be substituted with halo, or R8 and R9 taken together with the nitrogen to which they are attached form a five-, six-, or seven-membered heterocyclic ring wherein the heterocyclic ring optionally has one to two additional heteroatoms selected from the group consisting of oxygen, sulfur and N(Y) and wherein the carbon atoms of the heterocyclic ring is optionally substituted with one or two R13; wherein Y is absent or R14; wherein R10 and R11 is independently H, or C1-4 alkyl; R13 is C1-6 alkyl, C3-4 cycloalkyl, C2-4 alkyl substituted with xe2x80x94OH, xe2x80x94O(C1-4 alkyl), xe2x80x94O(C1-4 alkyl)xe2x80x94NR10R11 or xe2x80x94CO2R5, xe2x80x94OH, or oxo (xe2x95x90O); R14 is H, C1-6 alkyl, C3-6 cycloalkyl, C2-4 alkyl substituted with xe2x80x94OH, xe2x80x94O(C1-4 alkyl), xe2x80x94O(C1-4 alkyl)xe2x80x94NR10R11 or xe2x80x94CO2R5, xe2x80x94COOR7, xe2x80x94OH, or oxo (xe2x95x90O).
A specific value for R3 includes xe2x80x94(CH2)2xe2x80x94NR8R9, wherein R8 and R9 is independently H, C1-4 alkyl, C2-4 alkyl substituted with xe2x80x94OH, xe2x80x94CHO (with the proviso that only one of the R8 and R9 is xe2x80x94CHO, the other one is hydrogen), or R8 and R9 taken together with the nitrogen to which they are attached form piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, piperazinyl or azetidinyl, wherein one of the nitrogen atoms on the piperazinyl ring is substituted with H, C1-4 alkyl, or xe2x80x94CO2(C1-4 alkyl).
A specific value for R3 includes xe2x80x94(CH2)2xe2x80x94NR8R9, wherein R9 and R9 is independently H, methyl, ethyl, ethanol, isopropyl, or R8 and R9 taken together with the nitrogen to which they are attached form 1-piperazinyl, 4-methyl-1-piperazinyl, 4-tert-butyl-1-piperazinecarboxylate, 4-morpholinyl, 1-piperidinyl, 1-pyrrolidine or xe2x80x94CHO with the proviso that only one of the R8 and R9 is xe2x80x94CHO, the other one is hydrogen.
A specific value for R4 includes aryl, wherein aryl is defined as herein above.
A specific value for R4 includes substituted or unsubstituted phenyl.
A specific value for R4 includes heteroaryl.
A specific value for R4 includes pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, triazinyl, quinolinyl, thiophenyl, furanyl, or pyrrolyl,
A specific value for R4 is phenyl.
Examples of the present invention includes:
a) (S)-(+)-[(1-phenyl-1,2-dihydro[1,4]oxazino[2,3,4-jk]carbazol-7-yl)oxy]ethanamine,
b) (R)-(xe2x88x92)-[(1-phenyl-1,2-dihydro[1,4]oxazino[2,3,4-jk]carbazol-7-yl)oxy]ethanamine,
c) N,N-diethyl-2-[(1-phenyl-1,2-dihydro[1,4]oxazino[2,3,4-jk]carbazol-7-yl)oxy]-1-ethanamine,
d) [(1-phenyl-1,2-dihydro[1,4]oxazino[2,3,4-jk]carbazol-7-yl)oxy]ethanamine,
e) N-isopropyl-N-{2-[(1-phenyl-1,2-dihydro[1,4]oxazino[2,3,4-jk]carbazol-7-yl)oxy]ethyl}amine,
f) N-ethyl-2-[(1-phenyl-1,2-dihydro[1,4]oxazino[2,3,4-jk]carbazol-7-yl)oxy]-1-ethanamine,
g) 2-[(1-phenyl-1,2-dihydro[1,4]oxazino[2,3,4-jk]carbazol-7-yl)oxy]ethylformamide,
h) N-methyl-2-[(1-phenyl-1,2-dihydro[1,4]oxazino[2,3,4-jk]carbazol-7-yl)oxy]-1-ethanamine,
i) 2-[(8-chloro-1-phenyl-1,2-dihydro[1,4]oxazino[2,3,4-jk]carbazol-7-yl)oxy]-1-ethanamine,
j) 2-[(5-methyl-1-phenyl-1,2-dihydro[1,4]oxazino[2,3,4-jk]carbazol-7-yl)oxy]-1-ethanamine,
k) N-ethyl-2-[(5-methyl-1-phenyl-1,2-dihydro[1,4]oxazino[2,3,4-jk]carbazol-7-yl)oxy]-1-ethanamine,
l) tert-butyl 4-{2-[(1-phenyl-1,2-dihydro[1,4]oxazino[2,3,4-jk]carbazol-7-yl)oxy]ethyl}-1-piperazinecarboxylate,
m) 1-phenyl-1,2-dihydro[1,4]oxazino[2,3,4-jk]carbazol-7-yl 2-(1-piperazinyl)ethyl ether,
n) 2-(4-methyl-1-piperazinyl)ethyl 1-phenyl-1,2-dihydro[1,4[oxazino ]2,3,4-jk]carbazol-7-yl ether,
o) 2-(4-morpholin)ethl 1-phenyl-1,2-dihydro[1,4]oxazino[2,3,4]jk]carbazol-7-yl ether,
p) 1-phenyl-1,2-dihydro[1,4]oxazino[2,3,4-jk]carbazol-7-yl 2-(1-piperidinyl)ethyl ether,
q) 2-({2-[(1-phenyl-1,2-dihydro[1,4]oxazino[2,3,4-jk]carbazol-7-yl)oxy]ethyl}amino)-1-ethanol,
r) N,N-dimethyl-2-[(1-phenyl-1,2-dihydro[1,4]oxazino[2,3,4-jk]carbazol-7-yl)oxy]-1-ethanamine,
(s) 2-[(5-Methyl-1-phenyl-1,2-dihydro[1,4]oxazino[2,3,4-jk]carbazol-7-yl)oxy]-1-ethanamine,
(t) N,N-Diethyl-N-{4-[(1-phenyl-1,2-dihydro[1,4]oxazino[2,3,4-jk]carbazol-7-yl)oxy]butyl}-amine,
(u) N,N-Diethyl-N-{3-[(1-phenyl-1,2-dihydro[1,4]oxazino[2,3,4-jk]carbazol-7-yl)oxy]propyl}amine,
(v) [(2-{[(1R)-1-Phenyl-1,2-dihydro[1,4]oxazino[2,3,4-jk]carbazol-7-yl]oxy}ethyl)amino]ethanol, or pharmaceutically acceptable salt thereof.
It will be appreciated by those skilled in the art that compounds of the invention contain a chiral center, therefore, they may be isolated in optically active or racemic forms. Some compounds may exhibit polymorphism. It is to be understood that the present invention encompasses any racemic, optically active, polymorphic, tautomeric, or stereoisomeric form, or mixture thereof, of a compound of the invention, which possesses the useful properties described herein. It is well known in the art to prepare optically active forms (for example, by resolution of the racemic form by recrystallization techniques, by synthesis from optically-active starting materials, by chiral synthesis, or by chromatographic separation (using a chiral stationary phase, for example) and to determine 5-HT6 activity using the standard tests described herein, or using other similar tests which are well known in the art.
The following Schemes describe the preparation of compounds of the present invention. All of the starting materials are commercially available or prepared by procedures described in these schemes or by procedures that would be well known to one of ordinary skill in organic chemistry. The variables used in the Schemes are as defined above or as in the claims.
Chart A discloses several methods of preparing benzoxazine 6. Nitrophenol 1 can be alkylated with an alpha halo ketone 2 using a base such as sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, sodium hydride, and sodium hydroxide in solvents such as DMF, THF, acetone, dichloromethane, or acetonitrile to give nitro ether 3. Reduction of the nitro group of 3 with reducing agents such as hydrogen and palladium on carbon or tin (II) chloride or other reducing agents (see, for example, March, J. Advanced Organic Chemistry, 3rd ed., John Wiley and Sons: New York: 1985) gives oxazine imine 5, which upon further treatment with reducing agents such as hydrogen and palladium on carbon or sodium borohydride in solvents such as ethanol, methanol, and water gives benzoxazine 6. Alternatively, oxazine imine 5 is prepared from amino phenol 4 and alpha halo ketone 2 in the presence of a phase transfer catalyst and dichloromethane and aqueous potassium carbonate (see Sabitha and Rao, Synthetic Communications 1987, 17, 341).
Benzoxazine 6 contains a chiral center. The individual enantiomers may be obtained by several methods. One method is chromatography on a chiral stationary phase to give the individual enantiomers (see Chiral Separations by Liquid Chromatography, Ahuja, S., ed., American Chemical Society, Washington, D.C.: 1991, and Chiral Separations by HPLC: Application to Pharmaceutical Compounds, Krstulovic, A. M., ed., Ellis Norwood Limited: Chicester: 1989). Another method of obtaining the enantiomers is through reduction of oxazine imine 5 with chiral reducing agents used either stoichiometrically or catalytically. One method of using a stoichiometric amount of a chiral reducing agent is to prepare the reducing agent from sodium borohydride and an N-protected L- or D-amino acid (see Atarashi, et al. J. Heterocyclic Chem. 1991, 28, 329 and Yamada et al. J. Chem. Soc. Perkin Trans. I 1983, 265). For example, the use of CBZ-L-proline in the reagent prepared according to these references gives (+)-benzoxazine 6 as the major enantiomer. Another method of preparing benzoxazine 6 in chiral form is through the use of a chiral catalyst in the presence of a reducing agent as set forth by Noyori et al. (J. Am. Chem. Soc. 1996, 118, 4916), Buchwald et al. (J. Am. Chem. Soc. 1996, 118, 6784 and Ang. Chem. Int. Ed. Engl. 1998, 37, 1103) and others. Structures 6, 7, 8 and 9 are either racemics or individual enantiomers in Chart A and the subsequent reactions schemes. For illustration, only the racemic form is depicted.
Next, benzoxazine 6 is stirred in an acidic solvent such as TFA, acetic acid, or aq. sulfuric acid. A nitrite such as sodium nitrite, isoamylnitrite, t-butylnitrite, or n-butylnitrite is added to give N-nitrosoamine 7. N-nitrosoamine 7 is reduced with lithium aluminum hydride in ether or THF to give the hydrazine 8, which can be reacted with cyclohexane-1,3-dione under Fischer indole conditions to give the oxotetrahydrooxazinocarbazole 9 (see Sundberg, R. J.; Indoles, Academic Press: London; 1996, and in Hughes, D. L. Progress in the Fischer Indole Reaction: A Review. Org. Prep. Proceed. Int. 1993, 25, 609-632). When 9 is racemic, it is conveniently separated into its enantiomers by chromatography on a column packed with a chiral stationary phase and using an eluant such as isopranol/hexane. (see Chiral Separations by Liquid Chromatography, Ahuja, S., ed., American Chemical Society, Washington, D.C.: 1991, and Chiral Separations by HPLC: Application to Pharmaceutical Compounds, Krstulovic, A. M., ed., Ellis Norwood Limited: Chicester: 1989).
Charts B, C, and D depict only the racemate, but the methods given apply as well to the individual enantiomers.
In Chart B, phenol 12 can be prepared from structure 9 in a single step using Raney nickel in solvents such as cumene, mesitylene, 1,2,3-trimethylbenzene, 1,2,4-trimethylbenzene, decalin, and diphenyl ether at temperatures between 130-270xc2x0 C. to give phenol 12 directly. A second method is heating 9 in 2-(ethoxyethoxy)ethanol at about 160-210xc2x0 C. in the presence of Pd on carbon or Darco, or a mixture thereof (see European patent EP839806). Alternatively, structure 9 is first treated with a copper (II) halide, preferably CuCl2 or CuBr2, in either their anhydrous or hydrated form, in solvents such as ethylene glycol, ethylene glycol/doixane, ethylene glycol/THF, DMF, acetonitrile, ethyl acetate, chloroform, acetic acid, or acetic acid/water at temperatures between 40xc2x0 C. and 120xc2x0 C. to give halo ketones 10 and 11. For a reference to this reaction, see Matsumoto, M.; Ishida, Y.; Watanabe, N. Heterocycles 1985, 23, 165-170. A mixture of mono and dihalo ketones 10 and 11, respectively, are usually obtained with halogenating reagents such as the copper halides. Halo ketones 10 and 11 may be separated by chromatography on silica gel and carried on to 12 and 13, or they may be carried forward as a mixture in the next step and separated in at that time. The halo ketones 10 and 11 (separately or together) are then treated with lithium chloride or lithium bromide (anhydrous LiCl or LiBr are preferred, but hydrated forms also may be used) in the presence of lithium carbonate, or with potassium carbonate with or without added lithium halide salts in a solvent such as DMF at 100-270xc2x0 C. to give phenols 12 and 13. Alternatively, 9 may be alkylated using an alkylating agent such as methyl iodide in the presence of a base such as NaH, KO-t-Bu, or LDA in solvents such as THF at temperature ranging from about xe2x88x9278xc2x0 C. to room temperature to give 10, which may be converted to 12 using the methods described for the direct conversion of 9 to 12.
Phenols 12 and 13 may be alkylated with various alkylating agents to give oxazino amines 16, 17, 19, 20, and 24 directly or after several steps. Which method is used will depend on the type of amine which is desired and on the availability of alkylating agents and amines.
As shown in Chart B phenols 12 and 13 are alkylated with dialkylaminoalkylchlorides in the presence of bases such as sodium hydride, potassium carbonate, cesium carbonate, or sodium carbonate in solvents such as DMF, acetonitrile, or acetone at room temperature to 120xc2x0 C. using methods well-known to those versed in the art to give oxazine amines 16 and 17. Alternatively, phenols 12 and 13 are alkylated with chloro or bromoalkylnitrile in the presence of bases such as sodium hydride, potassium carbonate, cesium carbonate, or sodium carbonate in solvents such as DMF, acetonitrile, or acetone to give nitrites 14 and 15. Reduction of the nitrile with borane in THF or borane-methyl sulfide complex in THF at room temperature to 80xc2x0 C. gives oxazino amines 16 and 17.
Chart C discloses further functionalization of oxazino amine 16 (or 17) by several methods. One method is acylation with acylation agents such as ethyl formate, acetic anhydride, and the like to give acyl oxazinocarbazole 18. The carbonyl group of acyl oxazinocarbazole 18 is reduced to an alkyl group using reagents such as borane in THF or borane-methyl sulfide complex in THF at room temperature to 80xc2x0 C. to give alkylamino oxazinocarbazole 19. Another method is reduction using lithium aluminum hydride in ethereal solvents to effect the reduction of 18 to alkylamino oxazinocarbazole 19. Another method for the preparation of oxazinocarbazole 19 is reductive amination of 16 with an equivalent amount of an aldehyde or ketone in the presence of reducing agents such as sodium cyanoborohydride or sodium triacetoxyborohydride in solvents such as dichloromethane, dichloroethane, and THF at 0 to 80xc2x0 C., or Pd/C under a hydrogen atmosphere in solvents such as methanol, ethanol, or ethyl acetate, to give 19. A third method is alkylation of oxazino amine 16 with alkyl halides or mesylates or tosylates in the presence of base in solvents such as THF, acetonitrile, dichloromethane, DMF and the like using methods well known to those versed in the art, to give 19. In Chart C, Q is hydrogen, alkyl, or aryl. Z is hydrogen or alkyl. X is halo or sulfonate.
When dialkylamino oxazinocarbazole 20 is desired, a second equivalent of the same or a different aldehyde or alkylating agent is added to alkylamino oxazinocarbazole 19 using the conditions described above. Alternatively, excess alkylating agent or aldehyde or ketone may be used starting with 16 to give 20 directly.
Chart D describes two other methods of preparing mono or dialkylamino oxazines 24. Phenol 12 (or 13) is alkylated with halo alkyl halides in the presence of bases such as potassium carbonate, cesium carbonate, and NaH in solvents such as DMF, acetonitrile, THF, dichloromethane, and acetone at room temperature to 120xc2x0 C. to give oxazine halide 21. Halo oxazine 21 is then treated with an amine in the presence of a base such as potassium carbonate, TEA, DIEA in solvents such as DMF, acetonitrile, THF, dichloromethane, or acetone at room temperature to 120xc2x0 C. to give amino oxazine 24. Another route to amino oxazine 24 is by way of alkylation of phenol 12 with hydroxyalkyl halide to give oxazine alcohol 22. The alcohol group is converted to a leaving group with methane sulfonyl halide or toluene sulfonyl halide to give oxazine sulfonate 23. The O-sulfonate group is then displaced by amines to give amino oxazine 24.
Pharmaceutically acceptable salts may be obtained using standard procedures well known in the art, for example by mixing a compound of the present invention with a suitable acid.
Compounds of the present invention can conveniently be administered in a pharmaceutical composition containing the compound in combination with a suitable excipient. Such pharmaceutical compositions can be prepared by methods and contain excipients which are well known in the art. A generally recognized compendium of such methods and ingredients is Remington""s Pharmaceutical Sciences by E. W. Martin (Mark Publ. Co., 15th Ed., 1975). The compounds and compositions of the present invention can be administered parenterally (for example, by intravenous, intraperitoneal or intramuscular injection), topically, orally, or rectally.
For oral therapeutic administration, the active compound may be combined with one or more excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like. Such compositions and preparations should contain at least 0.1% of active compound. The percentage of the compositions and preparations may, of course, be varied and may conveniently be between about 2 to about 60% of the weight of a given unit dosage form. The amount of active compound in such therapeutically useful compositions is such that an effective dosage level will be obtained.
The tablets, troches, pills, capsules, and the like may also contain the following: binders such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, fructose, lactose or aspartame or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring may be added. When the unit dosage form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier, such as a vegetable oil or a polyethylene glycol. Various other materials may be present as coatings or to otherwise modify the physical form of the solid unit dosage form. For instance, tablets, pills, or capsules may be coated with gelatin, wax, shellac or sugar and the like. A syrup or elixir may contain the active compound, sucrose or fructose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring such as cherry or orange flavor. Of course, any material used in preparing any unit dosage form should be pharmaceutically acceptable and substantially non-toxic in the amounts employed. In addition, the active compound may be incorporated into sustained-release preparations and devices.
The compounds or compositions can also be administered intravenously or intraperitoneally by infusion or injection. Solutions of the active compound or its salts can be prepared in water, optionally mixed with a nontoxic surfactant. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, triacetin, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
Pharmaceutical dosage forms suitable for injection or infusion can include sterile aqueous solutions or dispersions or sterile powders comprising the active ingredient which are adapted for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions, optionally encapsulated in liposomes. In all cases, the ultimate dosage form should be sterile, fluid and stable under the conditions of manufacture and storage. The liquid carrier or vehicle can be a solvent or liquid dispersion medium comprising, for example, water, ethanol, a polyol (for example, glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, nontoxic glyceryl esters, and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the formation of liposomes, by the maintenance of the required particle size in the case of dispersions or by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, buffers or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.
Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filter sterilization. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and the freeze drying techniques, which yield a powder of the active ingredient plus any additional desired ingredient present in the previously sterile-filtered solutions.
For topical administration, the present compounds may be applied in pure form, i.e., when they are liquids. However, it will generally be desirable to administer them to the skin as compositions or formulations, in combination with a dermatologically acceptable carrier, which may be a solid or a liquid.
Useful solid carriers include finely divided solids such as talc, clay, microcrystalline cellulose, silica, alumina and the like. Useful liquid carriers include water, alcohols or glycols or water-alcohol/glycol blends, in which the present compounds can be dissolved or dispersed at effective levels, optionally with the aid of non-toxic surfactants. Adjuvants such as fragrances and additional antimicrobial agents can be added to optimize the properties for a given use. The resultant liquid compositions can be applied from absorbent pads, used to impregnate bandages and other dressings, or sprayed onto the affected area using pump-type or aerosol sprayers. Thickeners such as synthetic polymers, fatty acids, fatty acid salts and esters, fatty alcohols, modified celluloses or modified mineral materials can also be employed with liquid carriers to form spreadable pastes, gels, ointments, soaps, and the like, for application directly to the skin of the user.
Useful dosages of the compounds of formula I can be determined by comparing their in vitro activity, and in vivo activity in animal models. Methods for the extrapolation of effective dosages in mice, and other animals, to humans are known to the art; for example, see U.S. Pat. No. 4,938,949.
The compound is conveniently administered in unit dosage form; for example, containing about 0.05 mg to about 500 mg, conveniently about 0.1 mg to about 250 mg, most conveniently, about 1 mg to about 150 mg of active ingredient per unit dosage form. The desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more sub-doses per day. The sub-dose itself may be further divided, e.g., into a number of discrete loosely spaced administrations.
The compositions can conveniently be administered orally, sublingually, transdermally, or parenterally at dose levels of about 0.01 to about 150 mg/kg, preferably about 0.1 to about 50 mg/kg, and more preferably about 0.1 to about 30 mg/kg of mammal body weight.
For parenteral administration the compounds are presented in aqueous solution in a concentration of from about 0.1 to about 10%, more preferably about 0.1 to about 7%. The solution may contain other ingredients, such as emulsifiers, antioxidants or buffers.
The exact regimen for administration of the compounds and compositions disclosed herein will necessarily be dependent upon the needs of the individual subject being treated, the type of treatment and, of course, the judgment of the attending practitioner.
Generally, compounds of the invention are 5-HT ligands. The ability of a compound of the invention to bind or act at a 5-HT receptor, or to bind or act selectively at a specific 5-HT receptor subtype can be determined using in vitro and in vivo assays that are known in the art. As used herein, the term xe2x80x9cbind selectivelyxe2x80x9d means a compound binds at least 2 times, preferably at least 10 times, and more preferably at least 50 times more readily to a given 5-HT subtype than to one or more other subtypes. Preferred compounds of the invention bind selectively to one or more 5-HT receptor subtypes.
The ability of a compound of the invention to act as a 5-HT receptor agonist or antagonist can also be determined using in vitro and in vivo assays that are known in the art. The invention provides compounds of formula I that act as either agonists or as antagonists of one or more 5-HT receptor subtypes.
Growth of Cells and Membrane Preparation
Hela cells containing the cloned human 5-HT6 receptor were acquired from Dr. David R. Sibley""s laboratory in National Institute of Health (see Sibley, D. R., J. Neurochemistry, 66, 47-56, 1996). Cells were grown in high glucose Dulbecco""s modified Eagle""s medium, supplemented with L-glutamine, 0.5% sodium pyruvate, 0.3% penicillin-streptomycin, 0.025% G-418 and 5% Gibco fetal bovine serum and then were harvested, when confluent, in cold phosphate buffered saline.
Harvested intact cells were washed once in cold phosphate-buffered saline. The cells were pelleted and resuspended in 100 ml of cold 50 mM Tris, 5 mM EDTA and 5 mM EGTA, pH 7.4. Homogenization was with a Vir Tishear generator, 4 cycles for 30 seconds each at setting 50. The homogenized cells were centrifuged at 700 RPM (1000xc3x97g) for 10 minutes and the supernatant was removed. The pellet was resuspended in 100 ml of the above buffer and rehomogenized for 2 cycles. The rehomogenized cells were then centrifuged at 700 RPM (1000xc3x97g) for 10 minutes and the supernatant was removed. The combined supernatant (200ml) was centrifuged at 23,000 RPM (80,000xc3x97g) for 1 hour in a Beckman Rotor (42.1 Ti). The membrane pellet was resupended in 50-8-ml of assay buffer containing HEPES 20 mM, MgC12 10 mM, NaCl 150 mM, EDTA 1 mM, pH 7.4 and stored frozen in aliqouts at xe2x88x9270xc2x0 C.
5-HT6 Receptor Binding Assay
The radioligand binding assay used [3H]-lysergic acid diethylamide (LSD). The assay was carried out in Wallac 96-well sample plates by the addition of 11 xcexcl of the test sample at the appropriate dilution (the assay employed 11 serial concentrations of samples run in duplicate), 11 xcexcl of radioligand, and 178 xcexcl of a washed mixture of WGA-coated SPA beads and membranes in binding buffer. The plates were shaken for about 5 minutes and then incubated at room temperature for 1 hour. The plates were then loaded into counting cassettes and counted in a Wallac MicroBeta Trilux scintillation counter.
Binding Constant (Ki) Determination
Eleven serial dilutions of test compounds were distributed to assay plates using the PE/Cetus Pro/Pette pipetter. These dilutions were, followed by radioligand and the bead-membrane mixture prepared as described above. The specifically bound cpm obtained were fit to a one-site binding model using GraphPad Prism ver. 2.0. Estimated IC50 values were converted to Ki values using the Cheng-Prusoff equation (Cheng, Y. C. et al., Biochem. Pharmacol., 22, 3099-108, 1973). The Ki values obtained from the assay are shown in